This invention relates to the treatment and control of hyperglycemia, such as occurs in non-insulin-dependent diabetes mellitus (NIDDM). This invention also relates to treatment and control of hyperlipidemia.
The disease, diabetes mellitus, is recognized in two forms. Type I diabetes requires exogenous insulin for control of the disease because it appears that endogenous production of insulin by the Isles of Langerhans in the pancreas is extremely poor or non-existent. Type I diabetes is often referred to as insulin-dependent diabetes mellitus (IDDM). Type II, non-insulin-dependent diabetes mellitus (NIDDM), is characterized by defects of insulin sensitivity in peripheral tissues such as adipose tissue and muscle, as described by J. E. Gerich in New Engl. J. Med., 321, 1231-1245 (1989).
Hyperlipidemia is often observed in diabetics (Diabetes Care, 18, Supplement 1, 86-93, 1995). The combination of hyperlipidemia and hyperglycemia greatly increases the risk of cardiovascular diseases in diabetics. Successful treatment of hyperlipidemia and hyperglycemia in diabetics is needed urgently.
Blank reviewed hypoglycemic agents (Burger""s Medicinal Chemistry, 4th Ed., Part II , John Wiley and Sons, N.Y., 1979, 1057-1080). Newer hypoglycemic agents were reviewed by Hulin in Progress in Medicinal Chemistry, 31, ed. G. P. Ellis and D. K. Luscombe, Elsevier Publishing Co., 1993.
Currently, partial control of NIDDM is achieved by a diet and exercise regimen, by administration of exogenous insulin, by administration of hypoglycemic agents, (e.g. the sulfonylureas), or by some combination of these protocols. Sulfonylureas, such as chloropropamide, acetohexamide and tolbutamide, are useful orally-effective hypoglycemic agents achieving success in the control of NIDDM in a number of patients. However, drugs currently available for the control of the hyperglycemia associated with type II diabetes mellitus (NIDDM) possess significant liabilities or limitations of efficacy. (Ellingboe, et al., J. Med. Chem. 36:2485-2493, 1993). Considerable effort has been expended toward developing novel, orally-administered antihyperglycemic drugs. A preferred therapeutic approach for treating NIDDM incorporates drugs that counteract insulin resistance rather than those that stimulate endogenous insulin secretion. (J. R. Colca and D. R. Morton, New Antidiabetic Drugs, ed. C. J. Bailey and P. R. Flatt, Smith-Gordon and Company, Ltd., London, Chapter 24, 1990). Drugs that treat insulin resistance are called insulin sensitivity enhancers.
Sato, Y, et al. (Diabetes Research and Clinical Practice, 12:53-60, 1991) described the hypoglycemic effect of D-phenylalanine derivatives. In normal dogs, the hypoglycemic activity of the compound was greater than that of tolbutamide but less than that of glibenclamide. The compounds exerted a rapid hypoglycemic effect and improved glucose tolerance in genetically diabetic KK mice and in streptozotocin-treated rats. Yamasaki, et al. disclosed a group of 2-quinolone derivatives showing antidiabetic activity in NIDDM (WO 92/21342).
Some known hypoglycemic compounds also reduce serum cholesterol or triglyceride levels. (Clark, et al., U.S. Pat. No. 5,036,079). The combination of these biological activities in one compound is particularly advantageous because diabetics are highly susceptible to hyperlipidemia. Hulin, in U.S. Pat. No. 5,306,726, claimed phenylpropionic acid derivatives and disclosed compounds that had hypoglycemic and hypocholesterolemic activity useful for the treatment of diabetes and atherosclerosis. Miyata, et al. found a class of phosphonic diester derivatives useful for treating diabetes and hyperlipidemia (WO 93/23409). Hypolipidemic amino acid derivatives were disclosed in JA-028189. Highly substituted aryl ethers of tyrosine were reported to have hypocholesterolemic activity (J. Med. Chem., 38:695-707, 1995). No aklyl ethers of tyrosine were disclosed.
Pyrazole compounds have been shown to have hypoglycemic effect. For example, U.S. Pat. No. 5,183,825 issued Feb. 2, 1993 disclosed the use of 4-Arylmethyl-5-alkyl-3H-pyrazol-3-ones as hyperlipidermia.
The present invention provides novel pyrazolones and pyrazolines useful in the treatment of hyperglycemia and/or hyperglycemia.
The present invention is also a method of use of novel pyrazolones and/or pyrazolines in the treatment of hyperlipidemia and/or hyperglycemia.
The present invention also provides a pharmaceutical composition containing a pyrazolone and/or pyrazoline compound of the invention useful for the treatment of non-insulin dependent diabetes mellitus (NIDDM).
The present invention provides novel compounds having utility as hypoglycemic and hypolipidemic agents of formula I; 
wherein:
R1, R2, R3, and R4 are independently alkyl, aryl aralkyl, heteroaryl, heteroalkyl fragments of 1-20 atoms (including, but not limited to, carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, halogen) with or without substituents; Z1 is variously hydrogen, oxygen, sulfur, nitrogen; The dashed bonds are variously single or double; n is an integer from zero to 2.
The terms used to describe the instant invention have the following meanings herein.
A xe2x80x9cmammalxe2x80x9d is an individual animal that is a member of the taxonomic class mammalia. The class mammalia includes humans, monkeys, chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice, and rats.
xe2x80x9cC1-4 alkylxe2x80x9d refers to a straight or branched alkyl radicals having 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, or t-butyl.
xe2x80x9cC1-4 alkoxyxe2x80x9d refers to a straight or branched chain alkyl radicals attached to oxygen having 1 to 4 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, or t-butoxy, and the like.
The terms xe2x80x9cactive ingredientxe2x80x9d and xe2x80x9cactive compoundxe2x80x9d as used herein are synonymous and refer to a compound(s) of the present invention as represented by formula I or its pharmaceutically acceptable salts or prodrug individually contained or combined with other compound(s) of formula I in a formulation of the invention.
The term xe2x80x9caralkylxe2x80x9d refers to an aryl(C1-C6-alkyl) group.
The term xe2x80x9carylxe2x80x9d refers to a substituted or unsubstituted aromatic or heteroaromatic radical (wherein the terms xe2x80x9caromatic groupxe2x80x9d and xe2x80x9cheteroaromatic groupxe2x80x9d refer to common aromatic rings having 4n+2 pi electrons in a monocyclic or bicyclic conjugated system) selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl 3-thienyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 1-naphthyl, 2-naphthyl, 2-benzofuryl, 3-benzofuryl, 4-benzofuryl, 5-benzofuryl, 6-benzofuryl, 7-benzofuryl, 2-benzothieny, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl, 6-benzothienyl, 7-benzothienyl, 1-indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl and 7-indolyl. Aryl groups may be optionally substituted at one or two carbon atoms of the aryl group, and may be with C1-4 alkyl, C1-4 alkoxy, halogen, xe2x80x94NO2, xe2x80x94CN, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94SO3H, xe2x80x94SO2NH2 or trifluoromethyl. Examples of substituted aryl groups are 4-methyl-3-furyl, 3,4-dimethyl-2-thienyl, 2,4-dimethyl-3-thienyl, 3-ethoxy-4-methyl-2-benzofuryl, 2-cyano-3-benzofuryl, 4-trifluoromethyl-2-benzothienyl, 2-chloro-3-benzothienyl, 3,4-dichloro-2-pyridyl, 2-bromo-3-pyridyl, 2-fluoro-4-pyridyl, 4-fluoro-2-furyl, 2-carboxyphenyl, 4-carboxamidophenyl, 3-trifluoromethylphenyl, 2-bromo-1-naphthyl, 2,3-dimethyl-1-naphthyl, 3-carboxy-2-naphthyl, 5-carboxy-8-chloro-1-naphthyl, 3-ethyl-2-furyl, 8-fluoro-2-naphthyl, 5-trifluoromethyl-2-naphthyl, 6-ethoxy-2-naphthyl, 6,7-dimethoxy-2-naphthyl, 3-carboxy-2-naphthyl, and the like.
The term, xe2x80x9calkylxe2x80x9d by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tertiary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl.
The term, xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers.
The term, xe2x80x9chydrocarbylxe2x80x9d means an organic group containing only carbon and hydrogen.
The term, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo, or iodo. The term, xe2x80x9cheterocyclic radicalxe2x80x9d, refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo[1.2-a]pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pirydinyl, dipyridylyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and quinoxalinyl.
The terms xe2x80x9calkylheterocyclicxe2x80x9d and xe2x80x9carylheterocyclicxe2x80x9d refer to radicals formed respectively by the bonding of a substituted or unsubstituted alkyl radical or aryl radical to a heterocyclic radical such that a news radical is generated with the reactive terminus at the alkyl or aryl group respectively.
The term xe2x80x9camino protecting groupxe2x80x9d as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reaction(s) are carried out at other functional groups of the compound. Examples of such amino-protecting groups include the formyl group, the phthalimido group, the trichloroacetyl group, the chloroacetyl, bromoacetyl and iodoacetyl groups, urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 2-(4-xenyl)iso-propoxycarbonyl, 1,1-diphenyleth-1-yloxycarbonyl, 1,1-diphenylprop-1-yloxycarbonyl, 2-phenylprop-2-yloxycarbonyl, 2-(p-toluyl)prop-2-yloxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcylcopentanyloxycarbonyl, cyclohexanyloxycarbonyl, 1-methylcyclohexanyloxycarbonyl, 2-methylcyclohexanyloxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (xe2x80x9cFMOCxe2x80x9d), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-en-3-yloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, 4-(decyloxy)benzyloxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, and the like; the benzoylmethylsulfonyl, the 2-(nitro)phenylsulfenyl group, the diphenylphosphine oxide group and like amino protecting groups. The species of amino protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Similar amino protecting groups used in the cephalosporin, penicillin, and peptide arts are also embraced by the above terms. Further examples of groups referred to by the above terms are described by J. S. Barton, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 2, and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, Chapter 7 and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., John Wiley and Sons, New York, N.Y., 1991. The related term xe2x80x9cprotected aminoxe2x80x9d defines an amino group substituted with an amino protecting group discussed above.
The term xe2x80x9ccarboxy protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups of the compound. Examples of such carboxylic acid protecting groups include benzyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, pentamethylbenzyl, 3,4-methylenediozybenzyl, benzyhydryl, 4,4xe2x80x2-dimethoxybenzhydryl, 2,2,4,4xe2x80x2-tetramethoxybenzhydryl, t-butyl, isobutyl, n-butyl, propyl, isopropyl, ethyl, methyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, trimethylsilyl, t-butyldimethylsilyl, phenyacyl, 2,2,2-trichloroethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, or 1-(trimethylsilylmethyl)prop-1-en-3-yl, and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction(s) on other positions of the molecule and can be removed at the appropriate point without disrupting the remainder of the molecule. Carboxy protecting groups similar to those used in the cephalosporin, penicillin, and peptide arts can also be used to protect a carboxy group substituent of the compounds provided herein. Further examples of these groups are found in E. Haslam, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1981, Chapter 5 and T. W. Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd Ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 5.
The term xe2x80x9cprodrugsxe2x80x9d as used herein defines derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Derivatives of the compounds of this invention have activity in both their acid and base derivative forms, but the acid derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters. Particularly preferred esters as prodrugs are methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and morpholinoethyl.
The term xe2x80x9chydroxy activation agentxe2x80x9d refers to acid halides, and acid anhydrides that are capable of converting a hydroxyl group into a leaving group labile to base treatment or nucleophilic displacement. Typical hydroxy activation agents include, but are not limited to sulfonating agents such as, methane sulfonyl chloride, p-toluenesulfonyl chloride, phenylsulfonyl chloride, trifluoromethylsulfonyl chloride, and the like, acylating agents such as isobutyl chloroformate, acetyl chloride, and the like, and halogenating reagents such as thionyl chloride, phosphorus tribromide, and the like.
The term xe2x80x9cactivated hydroxy groupxe2x80x9d refers to the moiety that results when a compound containing a hydroxy group is reacted with a hydroxy activating reagent e.g. the transformation from Oxe2x80x94H to o-methylsulfonyl, o,p-tolunesulfonyl, o-phenylsulfonyl, o-trifluoromethylsulfonyl, o-isobutylacetyl, o-acetyl, chloro, or bromo.
xe2x80x9cTherapeutically effective amountxe2x80x9d means that amount of a compound that will elicit the biological or medical response of a tissue, system, or mammal that is being sought by a researcher or clinician.
xe2x80x9cPharmaceutically acceptable saltxe2x80x9d refers to a salt of the compound of formula I, which is substantially non-toxic to mammals. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts, respectively. It should be recognized that the particular counter-ion forming a part of any salt of this invention is not of a critical nature, so long as the salt as a whole is pharmaceutically acceptable and as long as the counter-ion does not contribute undesired qualities to the salt as a whole.
Acids commonly employed to form acid addition salts are inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids, such as, without limitation, p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
The present invention provides novel compounds having utility as hypoglycemic and hypolipidemic agents of formula I; 
wherein:
R1, R2, R3, and R4 are independently alkyl, aryl, aralkyl, heteroaryl, heteroalkyl radicals of 1-20 atoms (including, but not limited to, carbon, hydrogen, oxygen, nitrogen, sulfur, phosphorus, halogen) with or without alkyl, aryl, aralkyl or heterocyclic radical substituents; Z1 is independently selected from Hydrogen, oxygen, sulfur, or nitrogen; the dashed bond is a single or double bond; and
n is an integer from zero to 2 or a salt or prodrug thereof.
Preferred for the purpose of the present invention is a compound of formula II: 
wherein:
R1, R2, R3, and R4 are as described above, and Z1 is oxygen, sulfur, nitrogen or hydrogen connected by a single or double bond to form the carbonyl (Cxe2x95x90O), thiocarbonyl (Cxe2x95x90S), hydroxy (OH), thiol (SH) or amino (NH2) functional groups.
More preferred is a compound selected from the group of compounds depicted by formula III: 
wherein:
R1, R2, Z1 are as described above and R3, R4 are Hydrogen. Most preferred is a compound of formula IV 
wherein;
R2, R3 and R4 are hydrogen; and
Z1 is oxygen, NR5 or S, wherein R5 is selected from the group consisting of H, C1-C4 alkyl, phenyl or benzyl.
Exemplary of preferred compounds for the present invention is a compound selected from the group consisting of: 
Pharmaceutically acceptable acid addition salts of the compounds of formula I are also aspects of this invention. Examples of such pharmaceutically acceptable salts are, without limitation, the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, -hydroxybutyrate, glycollate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like salts of the compound of formula I. The preferred acid addition salts are those formed with mineral acids, such as, without limitation, hydrochloric acid, and hydrobromic acid, and those formed with organic acids, such as, without limitation, maleic acid and methanesulfonic acid.
Exemplary of compounds of formula I useful for the purposes of this invention include:
4-(4-[2-(2-Phenyl-4-oxazolyl)ethoxy]phenylsulfonyl)-1H,2H-prazolin-3-one; 4-(4-[2-(2-Phenyl-4-oxazolyl)ethoxy]phenylmethylsulfonyl)-1H,2H-prazolin-3-one; 3-(4-(2-Phenyl-4-oxazolyl)ethoxy)phenyl-4-methylsulfonyl-1H-1,2-pyrazoline; 2-Naphthylsulfonyl-pyrazolin-3-one; and 6-(2-Fluorobenzyloxy)-2-naphthylsulfonyl-pyrazolin-3-one.
Compounds of Formula I are readily prepared by standard chemical reactions generally known to skilled practitioners and are summarized in standard texts and reference works; e.g. and i.a.: March, Advanced Organic Chemistry, Wiley-Interscience, New York 1985; Katritzky, Handbook of Heterocyclic Chemistry, Pergamon Press, London 1985, Fieser and Fieser, Reagents for Organic Synthesis, Wiley Interscience, New York, 1968-1998
Additional useful references are contained in xe2x80x9cGeneral methods for the acylation of sulfonesxe2x80x9d, M. W. Thomasen, B. M. Handwerker, S. A. Katz, R. B. Belser, J. Org. Chem. 1988, 53, 906-907; N. N. Girotra, et.al., J. Med. Chem. 1992, 35, 3474-3482. For Example, Scheme I depicts the preparation of a typical candidate compound of the present invention by a sequence involving, first, nucleophilic displacement of an activated aromatic fluoride by an alkoxide (generated from an alcohol using a strong base such as sodium hydride and the like, in an indifferent solvent such as DMF) [March, pp 576-607], then acylation of the resulting sulfone (under the influence of a strong base such as sodium hydride and the like, in an indifferent solvent such as THF and the like) to produce a beta-sulfonyl ester. Subsequent condensation of the sulfonyl ester with a formamide acetal, such as DMA in a typical inert solvent such as THF at a moderately elevated temperature such as 50-60xc2x0 C. [Fieser and Fieser, 3, 115] produces a substituted acrylate ester which cyclizes upon treatment with a diatomic nucleophile such as hydrazine to produce a heterocyclic compound such as a pyrazolin-3-one. 
An alternate route to compounds of the present invention is depicted in Scheme 2, wherein the intermediate beta sulfonyl esters are secured by a sequence involving conversion of an alcohol to an isothiuronium salt by reaction with thiourea and a hydrohalic acid such as HBr in a convenient solvent mixture such as water/methanol, hydrolysis of the isothiuronioum halide to a thiol (which may or may not be isolated), and alkylation of the thiol with a substituted acid derivative such as methyl bromoacetate [Fieser, 1, 1165]. Subsequent oxidation of the resulting thio-oxy acid derivative with a reagent such as hydrogen peroxide affords a beta sulfonyl ester, used as described above. 
An example of the synthesis of candidate pyrazolines is depicted in Scheme 3, wherein a beta sulfonyl ketone is produced by the alkylation of an ester, such as a substituted benzoate, with an alkyl sulfone, such as dimethyl sulfone in the presence of a base such as sodium hydried in an indifferent solvent such as THF, at a convenient temperature such as 50-60xc2x0 C. Condensation of the sulfonyl ketone with a reagent such as DMA produces a substituted vinyl keto sulfone, which undergoes cyclization to a heterocycle such as a pyrazoline upon treatment with a diatomic nucleophile such as hydrazine. 
Aromatic phenols (including e.g., naphthols) may be used to produce candidate compounds of the present invention as illustrated in Scheme 4, wherein a substituted naphthol is converted to an aryl thioacetic acid derivative by means of a Newman Rearrangement [Fieser 2, 173]. Subsequent conversion to a pyrazolin-3-one then follows Scheme 2. The sequence may be carried out without purification of intermediates (cf Example 4) or by isolation and characterization of intermediates (cf Example 5). 
The compounds of the present invention can be administered in oral forms, such as tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. They may also be administered in parenteral forms, such as intravenous (bolus or infusion), intraperitoneal, subcutaneous, intramuscular, and the like forms, well known to those of ordinary skill in the pharmaceutical arts. The compounds of the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal delivery systems well-known to those of ordinary skill in that art.
A dosage regimen utilizing the compounds of the present invention is selected by one of ordinary skill in the medical or veterinary arts in view of a variety of factors, including without limitation, the species, age, weight, sex, and medical condition of the recipient, the severity of the condition to be treated, the route of administration, the level of metabolic and excretory function of the recipient, the dosage form employed, the particular compound and salt thereof employed, and the like.
The compounds of the present invention are preferably formulated prior to administration together with one or more pharmaceutically acceptable excipients. Excipients are inert substances such as, without limitation, carriers, diluents, flavoring agents, sweeteners, lubricants, solubilizers, suspending agents, binders, tablet disintegrating agents and encapsulating material.
Therefore, yet another embodiment of the present invention is a pharmaceutical formulation comprising a compound of the invention and one or more pharmaceutically acceptable excipients that are compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the compounds of the invention together with one or more pharmaceutically acceptable excipients therefor. In making the compositions of the present invention, the active ingredient may be admixed with a diluent, or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. The carrier may serve as a diluent, which may be solid, semi-solid, or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
For oral administration in the form of a tablet or capsule, the active ingredient may be combined with an oral, non-toxic, pharmaceutically acceptable carrier, such as without limitation, lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate, calcium phosphate, calcium sulfate, sodium carbonate, mannitol, sorbitol and the like; together with, optionally, disintegrating agents, such as, without limitation, maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginic acid, and the like; and optionally, binding agents, for example, without limitation, gelatin, acacia, natural sugars, beta-lactose, corn sweeteners, natural and synthetic gums, acacia, tragacanth, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like; and optionally, lubricating agents, for example, without limitation, magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodium benzoate, sodium acetate, sodium chloride, talc, and the like.
In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel composition of the instant invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter.
Sterile liquid formulations include suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both sterile water and sterile organic solvent.
The active ingredient can also be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil.
Preferably, the pharmaceutical formulation is in unit dosage form. A xe2x80x9cunit dosage formxe2x80x9d is a physically discrete unit containing a unit dose, suitable for administration in human subjects or other mammals. A unit dosage form can be a capsule or tablet, or a number of capsules or tablets. A xe2x80x9cunit dosexe2x80x9d is a predetermined quantity of the active compound of the present invention, calculated to produce the desired therapeutic effect, in association with one or more pharmaceutically acceptable excipients. The quantity of active ingredient in a unit dose may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the recipient. The dosage will also depend on the route of administration.
The oral route is most preferred. Typical oral dosages of the present invention, when used for the indicated effects, will range from about 0.01 mg per kg body weight per day (mg/kg/day) to about 50 mg/kg/day, preferably from 0.1 mg/kg/day to 30 mg/kg/day, and most preferably from about 0.5 mg/kg/day to about 10 mg/kg/day. The compounds of the present invention may be administered in a single daily dose, or the total daily dose may be administered in divided doses, two, three, or more times per day. Where delivery is via transdermal forms, of course, administration is continuous.
The human to whom the compounds and formulations of the present invention are administered is afflicted with a disease or condition in which blood glucose levels are not adequately controlled without medical intervention, but wherein there is endogenous insulin present in the human""s blood and or afflicted with a disease or condition wherein lipid levels are not adequately or desirably controlled as in hyperlipidemia. Non-insulin dependent diabetes mellitus (NIDDM) is a chronic disease or condition characterized by the presence of insulin in the blood, even at levels above normal, but resistance or lack of sensitivity to insulin action at the tissues. The compounds and formulations of the present invention are also useful to treat acute or transient disorders in insulin sensitivity, such as sometimes occur following surgery, trauma, myocardial infarction, and the like. The compounds and formulations of the present invention are also useful for lowering serum triglyceride levels. Elevated triglyceride level, whether caused by genetic predisposition or by a high fat diet, is a risk factor for the development of heart disease, stroke, and circulatory system disorders and diseases. The physician of ordinary skill will know how to identify humans who will benefit from administration of the compounds and formulations of the present invention.